We found that the use of erythropoiesis-stimulating agents in patients with cancer with anemia resulted in improved scores for several disease-specific measures of quality of life and decreased the use of blood transfusions. The magnitude of improvement in quality of life appeared clinically relevant and was relatively consistent across trials and instruments. However, the use of erythropoiesis-stimulating agents led to an increased risk of all-cause mortality and a significant increase in the risk of serious adverse events. There was no evidence that treatment influenced the risk of cardiovascular events, admission to hospital or tumour response, although there was a borderline increase in the risk of hypertension associated with treatment.
The clinical relevance of the increases in the risk of death and serious adverse events must be considered in the context of the populations studied. Although the relative magnitude of increased risk was modest (15%–16%), the absolute increases in risk were substantial, which reflected the generally adverse underlying prognosis of people with cancer. It is possible, although speculative, that certain patients might choose a reduction in life expectancy in exchange for improved quality of life. However, all of the studies we included were of relatively short duration (median follow-up 12 weeks) and patients were generally aware of the treatment group to which they had been randomly assigned, which may have biased results in favour of treatment with erythropoiesis-stimulating agents.68
Future studies that address these knowledge gaps are required to determine whether the apparently increased risk of death associated with the use of erythropoiesis-stimulating agents might be offset by improved quality of life.
Current practices for the use of erythropoiesis-stimulating agents in people with cancer-related anemia are more restrictive than they once were. Guidelines from the American Society of Clinical Oncology72
indicate that the agents should not be used unless patients are receiving concurrent chemotherapy; however, they cautiously recommend their use when the hemoglobin level is less than or approaching 100 g/L (or 100–120 g/L in certain circumstances, including decreased cardiopulmonary reserve). The recently revised Health Canada label for darbepoetin is similar to the society’s criteria: it indicates that the agent should be used for cancer-related anemia under very specific conditions: the presence of nonmyeloid cancer; anemia due to chemotherapy; a hemoglobin level less than 100 g/L; and a target hemoglobin level of no more than 120 g/L. Although we identified 2 studies that reported mortality and met the last 3 conditions (and were therefore consistent with the American Society of Clinical Oncology’s criteria), both enrolled patients with a form of myeloid cancer (multiple myeloma). Therefore, none of the studies that reported mortality used erythropoiesis-stimulating agents in a manner consistent with the current Health Canada label for darbepoetin. The Health Canada label for epoetin is similar to the label for darbepoetin; however, it is slightly less restrictive because it does not specify the hemoglobin level at which therapy should be initiated.
There is a striking lack of data to support Health Canada’s labels and the American Society of Clinical Oncology’s guidelines for the use of erythropoiesis-stimulating agents in people with cancer-related anemia. Although it is rational to restrict the use of a potentially harmful therapy, it is unclear whether following the directions in the current label permits the identification of patients with more favourable risk–benefit ratios. In particular, the fact that the risk of death was not significantly increased in the subgroup of trials in which participants met the American Society of Clinical Oncology’s criteria does not allay the safety concerns raised by the primary analysis.73,74
We found no evidence that the risks or benefits of treatment differed between patients who did or did not receive chemotherapy, or who did or did not meet the society’s criteria. This suggests that the most reliable estimates of benefit and harm in these subgroups are likely to be the pooled estimates obtained by combining results from all available trials.73,75
These findings suggest that erythropoiesis-stimulating agents should not be routinely used as an alternative to blood transfusion in patients with chemotherapy-induced anemia unless future studies document safety and clinical benefits in this population.
Strengths and limitations
Our study was an up-to-date, comprehensive systematic review of the clinical implications of use of erythropoiesis-stimulating agents for cancer-related anemia. We specifically addressed the potential clinical benefits of these agents when used according to current clinical practice guidelines. The studies we included were conducted on several continents over the last decade; enrolled more than 12 000 participants in total; involved 3 types of agents (epoetin alpha, epoetin beta and darbepoetin alpha); and focused on people with different types of cancer. Participants in randomized controlled trials tend to be less likely to experience adverse events and more likely to benefit from experimental therapies than unselected individuals with the same diseases. Despite this, the results of our review are likely to be externally valid.
Our study had limitations. Although we reduced the potential for bias by following recommendations for systematic reviews, the methodologic quality of the studies we included was poor to moderate. Also, many of the studies did not specify criteria for administering blood transfusions, which may have reduced internal validity. Second, we excluded studies with fewer than 30 participants; however, this unlikely influenced our conclusions, because the number of participants in the included trials was large. Third, the clinical effects of erythropoiesis-stimulating agents appeared to be homogeneous in the meta-regression analysis; however, this technique has limitations, including low statistical power and the ecological fallacy.76
Therefore, the risk–benefit ratio of erythropoiesis-stimulating agents in cancer-related anemia may vary in certain clinical populations.
Use of erythropoiesis-stimulating agents in patients with cancer-related anemia improved disease-specific measures of quality of life and decreased the use of blood transfusions. However, use of the agents led to an increased risk of all-cause mortality and serious adverse events. We found no evidence that the risks or benefits of treatment differed among patients who did or did not meet recently revised criteria for the use of these agents in patients with cancer. Our findings suggest that existing practice guidelines should be revised to recommend against the routine use of erythropoiesis-stimulating agents as an alternative to blood transfusion in patients with anemia related to cancer.